Understanding the underlying physics of the binding of small molecule ligands to protein active sites is one objective of computational chemistry and biology. While a wide range of techniques exist for calculating binding free energies, ranging from techniques that should be accurate in principle (e.g., free energy perturbation (FEP) theory) to relatively simple approximations based on empirically derived scoring functions, no completely satisfactory and robust approach has yet been developed. Furthermore, physical insight into the sources of binding affinity can be important for computing accurate numbers and can be valuable in many areas (e.g., the design of pharmaceutical candidate molecules).
It is widely believed that displacement of water molecules from the active site by the ligand is a major source of binding free energy. Water molecules solvating protein active sites are often entropically unfavorable due to the orientational and positional constraints imposed by the protein surface, or energetically unfavorable due to the water molecule's inability to form a full complement of hydrogen bonds when solvating the protein surface. This leads to free energy gains when a ligand that is suitably complementary to the active site displaces these waters into bulk solution, thus providing a relatively more favorable environment. FEP techniques can compute these free energy gains explicitly (within the accuracy of the force field used in the simulations) but are computationally expensive.
This computational expense has been a barrier to the adoption of FEP based techniques since, in some situations, computational techniques to predict protein-ligand binding free energies must take less wall clock time than synthesizing the small molecule and experimentally testing the binding affinity if these techniques are to have value, (e.g., in an industrial drug design setting). This demand for speed has motivated a broad use of continuum theories of hydration within empirical scoring functions to describe the contributions of the solvent to the binding affinity of the complex. However, it is still an unsettled question as to whether or not these continuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliably rank the binding affinities of a set of ligands for a given protein.